1-Aminomethyltricyclo[4.3.1.12,5 ]undecane and acid-addition salts thereof

ABSTRACT

1-Aminomethyltricyclo[4.3.1.1 2 ,5 ]undecane having the formula (I) and acid-addition salts thereof possess an excellent inhibitory effect on the growth of viruses even at a low concentration. ##STR1##

REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part application of Applicants'copending application Ser. No. 920,967 filed June 30, 1978, nowabandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel tricycloundecylamines and acid-additionsalts thereof, and more particularly, to1-aminomethyltricyclo[4.3.1.1.²,5 ]undercane represented by the formula(I) and acid-addition salts thereof. ##STR2##

2. Description of the Prior Art

The basic skeleton of the compound of the formula (I), that is,tricyclo[4.3.1.1²,5 ]undecane, was first reported as an isomerizationintermediate by N. Takaishi et al [N. Takaishi et al, J. Chem. Soc.,Perkin I, 789 (1975)]. In fact, the present inventers have disclosedseveral derivatives of tricyclo[4.3.2.1²,5 ]undecane such as1-hydroxytricyclo[4.3.2.1²,5 ]undecane (Japanese Patent Publication No.1978-46948), 1-halogenotricyclo[4.3.2.1²,5 ]undecane (Japanese PatentPublication No. 1978-46949), 1-amino[4.3.2.1²,5 ]undecane (JapanesePatent Publication No. 1978-50150) and 1-acetylaminotricyclo[4.3.2.1²,5]undecane (Japanese Patent Publications Nos. 1978-46950 and 1978-63362),but the compound of the formula (I) has not been discovered norsynthesized.

SUMMARY OF THE INVENTION

The compound of the formula (I) is structurally analogous to1-aminotricyclo[4.3.1.1²,5 ]undecane which has already been disclosed bythe present inventors (Japanese Patent Publication No. 1978-50150). Thecompound according to the invention exerts an inhibitory effect on thegrowth of viruses at a lower concentration than the earlier compound,1-aminotricyclo[4.3.1.1²,5 ]undecane. Particularly, the compound of theformula (I) possesses an excellent inhibitory effect on the growth ofNewcastle disease virus among Paramyxoviruses belonging to RNA virusesin chick embryo fibroblasts; that is, the compound of the formula (I)can inhibit the multiplication of viruses at about 1/6 and 1/2 theconcentrations of adamantylamine hydrochloride, which is well known tobe an anti-influenza viral agent, and 1-aminotricyclo[4.3.1.1²,5]undecane, respectively. Thus, the compound of the formula (I) is veryuseful as an ingredient of a medicine for human beings or a drug foranimals.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compound of the present invention represented by the formula (I) canbe synthesized, for instance, by reducing1-aminocarbonyltricyclo[4.3.1.1²,5 ]undecane of the formula (II) or1-cyanotricyclo[4.3.1.1²,5 ]undecane of the formula (III). ##STR3## Tothis reduction reaction are applicable any conventional reactionconditions which are effective in reducing amides and nitriles to theiramines. More specifically, the desired compound of the formula (I),1-aminomethyltricyclo[4.3.1.1²,5 ]undecane, is produced by reducing thecompound of the formulae (II) or (III) with lithium aluminum hydride insuch a solvent that is inert to both the starting material and the finalproduct, for example, ether, or by subjecting the compound of theformula (III) to catalytic hydrogenation.

1-Aminocarbonyltricyclo[4.3.1.1²,5 ]undecane, which is one of thestarting materials of the present invention, is prepared by ( 1)reacting endo-2-hydroxymethyltricyclo[5.2.1.0²,6 ]decane (disclosed inJapanese Patent Publication No. 1976-13760) with formic acid in thepresence of sulfuric acid to produce 1-carboxyltricyclo[4.3.1.1²,5]undecane, (2) halogenating the carboxylic acid with a conventionalhalogenating reagent such as thionyl chloride to product1-halogenocarbonyltricyclo[4.3.1.1²,5 ]undecane, and (3) then reactingthe acid halide with ammonia to produce1-aminocarbonyltricyclo[4.3.1.1²,5 ]undecane.

1-Cyanotricyclo[4.3.1.1²,5 ]undecane is pepared by dehydrating1-aminocarbonyltricyclo[4.3.1.1²,5 ]undecane, for example, by contactwith thionyl chloride.

The structure of the compound of the formula (I) has been confirmed byits elemental analysis and mass spectrum. As a result of these tests,the compound is recognized to possess one nitrogen atom per molecule andto have a molecular formula of C₁₂ H₂₁ N.

The infrared absorption spectrum of the compound shows peaks at3500-3100 and 1600 cm⁻¹ characteristic of amines and peaks due to theC-H stretching vibration characteristic of the carbon skeleton of thecompound of the formula (I). The substitution, position of the amino orcyano group in the starting compound of the formula (II) or (III) is the1-position, and the isomerization of the carbon skeleton, and therearrangement of substituents are certainly not expected to take placeunder the above reaction conditions. The structure of the compound ofthe formula (I) has been identified by the above analytical data.

Acid-addition salts of the compound of the formula (I) can be easilyproduced by neutralizing the compound of the formula (I) with acids.Suitable acids to be used include mineral acids such as hydrochloricacid, sulfuric acid, hydrobromic acid, hydroiodic acid, thiosulfuricacid and phosphoric acid; and organic acids such as carboxylic acids,for instance, formic acid, acetic acid, propionic acid, oxalic acid,citric acid and benzoic acid; and sulfonic acids, for instance,benzenesulfonic acid, methansulfonic acid and toluenesulfonic acid.Among these mineral acids particularly preferable are hydrohalogenicacids such as hydrochloric acid, hydrobromic acid and hydroiodic acid.

This invention is hereinafter described more specifically in terms ofsome Examples which, however, are meant purely to illustrate or explainand not to impose limitations upon the invention. Also given hereinbeloware several Reference Examples which are intended to make clear theadvantages of the invention.

EXAMPLE 1

4.5 g (0.023 mole) of 1-aminocarbonyltricyclo[4.3.1.1²,5 ]undecane in 60ml of tetrahydrofuran was added dropwise with stirring to 1.5 g (0.04mole) of lithium aluminum hydride in 90 ml of tetrahydrofuran. After theaddition is completed, the mixture was stirred under reflux for 1.5hours. After cooling, 1.5 ml of water, 1.5 ml of a 3 N sodium hydroxidesolution and 4.5 ml of water were in turn added to the resultingmixture. The reaction mixture was filtered and then concentrated toobtain 4.0 g of a colorless liquid. This liquid was distilled underreduced pressure to afford 3.2 g (yield: 77.7%) of1-aminomethyltricyclo[4.3.1.1²,5 ]undecane having a boiling point of 94°C. (0.6 mmHg).

IR (neat): 3500-3100, 3020, 2900, 1600, 1460 cm⁻¹.

MS (relative intensity): 179 (M⁺, 32), 147 (78), 107 (18), 95 (57), 93(41), 83 (32), 81 (60), 79 (31), 67 (100).

Hydrogen chloride gas was bubbled for 30 minutes into 3.2 g of the thusobtained 1-aminomethyltricyclo[4.3.1.1²,5 ]undecane in 50 ml of dryether. A precipitate was filtered off, washed with ether andrecrystallized from acetone to afford 3.0 g (yield: 80%) of1-aminomethyltricyclo[4.3.1.1²,5 ]undecane hydrochloride as colorlessneedles.

Elemental Analysis: as C₁₂ H₂₂ NCl; Calculated: C, 66.80; H, 10.28; N,6.49; Cl, 16.43%.

Found: C, 66.72; H, 10.32; N, 6.43; Cl, 16.52%.

IR (KBr): 3500, 2900, 1600, 1510 cm⁻¹.

MS (relative intensity): 179 (19), 162 (13), 149 (73), 107 (14), 95(40), 94 (15), 93 (31), 83 (24), 81 (47), 79 (25), 67 (100).

EXAMPLE 2

1.75 g (0.01 mole) of 1-cyanotricyclo[4.3.1.1²,5 ]undecane in 30 ml ofdry tetrahydrofuran was added dropwise to 0.45 g of lithium aluminumhydride suspended in tetrahydrofuran. After the addition, the resultingmixture was stirred under reflux for 2 hours. Thereafter, the sameprocedure was repeated as in Example 1 to afford1-aminomethyltricyclo[4.3.1.1²,5 ]undecane in a yield of 91%.

REFERENCE EXAMPLE 1

After a monolayer culture of a chick embryo fibroblast cell wasincubated in a test tube for 2 to 3 days, a Newcastle disease virussolution having about 128 HAU (hemagglutination unit) and a series ofsolutions of the test compounds were diluted stepwise. They wereincubated at 37° C. for 48 hours, and the virus multiplication wasmeasured with a hemagglutination test. The results obtained are shown inthe following table.

    ______________________________________                                                      Minimum growth-                                                                             Minimum cytotoxi-                                               inhibition con-                                                                             city concentration                                Test compounds                                                                              centration (μg/ml)                                                                       (μg/ml)                                        ______________________________________                                        1-Aminomethyltricyclo-                                                        [4.3.1.1.sup.2,5 ]undecane                                                    hydrochloride 40            40                                                (Present compound)                                                            1-Aminotricyclo-                                                              [4.3.1.1.sup.2,5 ]undecane                                                    hydrochloride 87            87                                                (Control)                                                                     Adamantylamine                                                                hydrochloride 250           250                                               (Control)                                                                     ______________________________________                                    

REFERENCE EXAMPLE 2

50 g of endo-2-hydroxymethyltricyclo[5.2.1.0²,6 ]decane dissolved in 200ml of formic acid was added dropwise with stirring to 400 ml of conc.sulfuric acid over a period of 2.5 hours while the temperature was keptat 0° to 10° C. The mixture was further stirred for 1 hour and allowedto stand. Separated solids were collected by filtration, washed withwater and dried to afford 58.2 g (yield: 99.6%) of tricyclo[4.3.1.1²,5]undecane-1-carboxylic acid. Recrystallization from n-hexane yielded awhite crystal having a melting point of 158.5° to 159.5° C.

Elemental Analysis: as C₁₂ H₁₈ O₂ ; Calculated: C, 74.19; H, 9.34%.

Found: C, 74.0; H, 9.24%.

IR (KBr): 3300-2700, 1685, 1460, 1405, 1290, 1270 cm⁻¹.

Mass Spectrum m/e (relative intensity): 194 (M⁺, 21), 149 (36), 127(40), 126 (25), 123 (26), 107 (15), 95 (20).

¹³ CNMR (CDCl₃, δC): 18.2 (t), 26.2 (t), 26.7 (t+t), 28.1 (t), 30.9 (t),32.4 (d), 40.3 (d), 42.9 (d), 44.9 (s), 185.6 (s)

REFERENCE EXAMPLE 3

68 ml of thionyl chloride was added dropwise to 46.0 g (0.24 mole) of1-carboxytricyclo[4.3.1.1²,5 ]undecane dissolved in 200 ml of benzene atroom temperature. The resulting mixture was refluxed for 1.5 hours, andexcess thionyl chloride and benzene were distilled off under reducedpressure. The residue obtained was fractionally distilled under reducedpressure to afford 47.0 g (yield: 92%) of1-chlorocarbonyltricyclo[4.3.1.1²,5 ]undecane having a boiling point of101° C. (1 mmHg).

Elemental Analysis: as C₁₂ H₁₇ OCl; Calculated: C, 67.76; H, 8.06; Cl,16.67%.

Found: C, 67.61; H, 8.12; Cl, 16.82%.

IR (neat): 3030, 2930, 2875, 2790, 2750 (sh), 1480, 990, 940, 860, 840,740 cm⁻¹.

REFERENCE EXAMPLE 4

10 g (0.047 mole) of 1-chlorocarbonyltricyclo[4.3.1.1²,5 ]undecane wasdissolved in 80 ml of anhydrous ether. Under cooling conditions,anhydrous ammonia was bubbled into the mixture for about 15 minutes todeposit a white precipitate. After being filtrated, the precipitate waswashed with ether, dried and recrystallized from a solution of benzeneand methanol to afford 8.7 g (yield: 96%) of1-aminocarbonyltricyclo[4.3.1.1²,5 ]undecane having a melting point of173°-174° C.

Elemental Analysis: as C₁₂ H₁₉ NO; Calculated: C, 74.57; H, 9.91; N,7.25%.

Found: C, 74.4; H, 9.8; N, 7.4%.

IR (KBr): 3450, 3030, 2925, 1650, 1610 cm⁻¹.

Mass Spectrum m/e (relative intensity): 193 (M⁺, 72), 149 (71), 126(31), 107 (19), 96 (10), 95 (13), 93 (29), 91 (17), 83 (27), 81 (51).

REFERENCE EXAMPLE 5

A mixture of 3.0 g (0.016 mole) of 1-aminocarbonyltricyclo[4.3.1.1²,5]undecane and 12 ml of thionyl chloride was refluxed with stirring for3.5 hours. After cooling, 20 ml of anhydrous benzene was added to thereaction mixture. The resulting mixture was condensed under reducedpressure, and excess thionyl chloride was distilled off to obtain 2.5 gof a pale yellow crystal. The thus obtained crystal was further purifiedby sublimation to afford 2.3 g (yield: 84.5%) of1-cyanotricyclo[4.3.1.1²,5 ]undecane having a melting point of 109°-110°C.

Elemental Analysis: as C₁₂ H₁₇ N Calculated: C, 82.23; H, 9.78; N,7.99%.

Found: C, 82.1; H, 9.8; N, 8.1%.

IR (KBr): 3030, 2925, 2225, 1435, 1115, 980 cm⁻¹.

Mass Spectrum m/e (relative intensity): 175 (M⁺, 31), 174 (14), 149(16), 147 (72), 146 (49), 107 (79), 95 (25), 81 (23), 79 (22), 67 (100).

What is claimed is:
 1. 1-Aminomethyltricyclo[4.3.1.1²,5 ]undecanerepresented by the formula (I) and acid-addition salts thereof. ##STR4##2. An acid-addition salt of 1-aminomethyltricyclo[4.3.1.1²,5 ]undecaneaccording to claim 1, wherein the acid-addition salt is a hydrogenhalide salt.